Postoperative complications and oncological outcomes after multimodal therapy of localised high risk soft tissue sarcoma

In einer retrospektiven Einzelinstitutstudie wurden onkologische Ergebnisse und schwerwiegende Wundkomplikationen bei Patienten mit lokalisiertem Weichteilsarkom analysiert, die mit multimodaler Therapie behandelt wurden. Für Patienten, die entweder mit einer neoadjuvanten oder einer adjuvanten Therapie behandelt wurden, zeigte sich kein statistisch signifikanter Unterschied in den onkologischen Ergebnissen. In Bezug auf die Verteilung der Risikofaktoren scheint es jedoch, dass Patienten, die mit einer neoadjuvanten Therapie behandelt wurden, ein höheres Risiko für schlechte onkologische Ergebnisse hatten, wenn man die statistisch signifikant höhere Rate von Tumoren über 5 cm berücksichtigt. Prognostische Faktoren für onkologische Ergebnisse wurden analysiert. Eine univariate Analyse zeigte schlechtere onkologische Ergebnisse bei Patienten mit großen und tief sitzenden Tumoren sowie retroperitonealem Weichteilsarkom. Positive Resektionsränder waren mit einer schlechteren LC verbunden, was zu einer schlechteren OS-Rate führte. Stratifiziert nach Strahlentherapiemodalität wurde jedoch nur bei Patienten, die mit einer adjuvanten Therapie behandelt wurden, ein Einfluss positiver Resektionsränder nachgewiesen. Darüber hinaus wurde in der multivariaten Analyse ein gutes pathologisches Ansprechen nach neoadjuvanter Therapie als einziger unabhängiger Faktor für ein besseres OS, DFS und DMFS identifiziert. Höhere Raten schwerer Wundkomplikationen wurden in der Gruppe der neoadjuvant behandelten Patienten nachgewiesen (ohne statistische Signifikanz). Risikofaktoren für schwerwiegende Wundkomplikationen wurden analysiert. Höhere Raten schwerer Wundkomplikationen wurden bei Weichteilsarkomen in der unteren Extremität beobachtet (insbesondere postoperative Serome und Wundheilungskomplikationen). Eine höhere Abszess- und Fistelrate wurde bei retroperitonealen Weichteilsarkomen nachgewiesen. Diabetes wurde als einer der wichtigsten Risikofaktoren für schwerwiegende Wundkomplikationen identifiziert (jedoch nur für infektassoziierte Komplikationen). Trotz relativ hoher Raten schwerer Wundkomplikationen in der Gruppe der mit neoadjuvanter Therapie behandelten Patienten, zeigte sich kein Einfluss der schweren Wundkomplikationen auf die onkologischen Ergebnisse für diese Gruppe. Aufgrund methodischer Einschränkungen und des retrospektiven Designs wurden Spättoxizitäten mit Ausnahme von pathologischen Frakturen und Osteonekrose nicht analysiert. Alle Patienten, bei denen eine pathologische Fraktur auftrat, wurden mit einer zusätzlichen Chemotherapie behandelt. Darüber hinaus wurde in der Gruppe der mit sequentieller Chemotherapie behandelten Patienten eine statistisch signifikant höhere Rate an pathologischen Frakturen festgestellt, was die Rolle der Chemotherapie als Risikofaktor für die Entwicklung einer pathologischen Fraktur möglich macht. In Anbetracht der onkologischen Ergebnisse, der Verteilung der wichtigsten Wundkomplikationen und ihres Einflusses auf die onkologischen Ergebnisse, erscheint es im Allgemeinen empfehlenswert, eine neoadjuvante Therapie bei Hochrisiko Weichteilsarkoma anzustreben. Diese Empfehlung gilt insbesondere für retroperitoneale, pelvine und abdominale Weichteilsarkome, bei denen eine hohe Dosis der postoperativen Strahlentherapie aufgrund von Einschränkungen der gefährdeten Organe häufig begrenzt ist. Die endgültige Entscheidung über die optimale Behandlung sollte jedoch unter Berücksichtigung verschiedener Patientenmerkmale und klinischer Tumoreigenschaften interdisziplinär getroffen werden

Hypofractionated preoperative radiotherapy for high risk soft tissue sarcomas in a geriatric patient population

BACKGROUND: Standard therapy for localised, resectable high risk soft tissue sarcomas consists of wide excision and radiotherapy over several weeks. This treatment schedule is hardly feasible in geriatric and frail patients. In order not to withhold radiotherapy from these patients, hypofractionated radiotherapy with 25 Gy in 5 fractions was evaluated in a geriatric patient population. PATIENTS AND METHODS: A retrospective analysis was performed of 18 geriatric patients with resectable high risk soft tissue sarcomas of extremities and thoracic wall. Wound healing and short term oncologic outcome were analysed. In addition, dose constraints for radiotherapy of the extremities were transferred from normofractionated to hypofractionated radiotherapy regimens. RESULTS: Feasibility was good with 17/18 patients completing treatment as planned. Wound healing complication rate was in the range of published data. Two patients developed local and distant recurrence, two patients isolated distant recurrences. No isolated local recurrences were observed. Keeping the constraints was possible in all cases without compromising the coverage of the target volume. CONCLUSIONS: Hypofractionated radiotherapy and surgery was well tolerated even in this specific patient population. With feasibility concerning early wound healing problems and adapted constraints, which allow for the treatment of most resectable extremity tumours, the concept warrants further evaluation in patients unfit for standard radiotherapy

MR Thermometry Data Correlate with Pathological Response for Soft Tissue Sarcoma of the Lower Extremity in a Single Center Analysis of Prospectively Registered Patients

Background: There is a strong biologic rationale for using locoregional hyperthermia in soft tissue sarcoma and a randomized trial reported significant improvements with hyperthermia. The aim of this study was to describe the opportunities of magnetic resonance (MR)-based thermometry in a cohort of soft tissue sarcoma patients undergoing combined radiotherapy and locoregional hyperthermia. Patients and Methods: For eleven evaluable patients, tumor volume (VTu) and a separate volume for temperature analysis with reliable temperature distribution (Vtherm) were contoured for every hyperthermia treatment (103 therapies). Temperature data were recorded for all tumors and were correlated with clinical features and pathologic response data. Results: Of 48 patients with high-risk soft tissue sarcomas treated with radio(chemo)therapy and locoregional hyperthermia, MR thermometry was possible in 11 (23%) patients. For all patients, the temperature superseded by 90% of VTu (T90(VTu)) and T90 (Vtherm) were in the range of 37–43 °C and 40–45 °C, respectively. Larger tumors tended to reach higher temperatures. For tumors showing a pathologic response in the resection specimen after preoperative treatment, temperature (T90 (Vtherm)) was significantly higher than in tumors without pathologic response. Conclusion: Lower extremity sarcomas undergoing preoperative treatment with locoregional hyperthermia are especially suitable for MR thermometry. MR thermometry is a promising non-invasive way for temperature measurement during locoregional hyperthermia, showing a positive dose-response relationship

Dose-escalated radiotherapy with simultaneous integrated boost for bone metastases in selected patients with assumed favourable prognosis

BACKGROUND: Stereotactic body radiotherapy (SBRT) concepts for dose escalation are increasingly used for bone metastases in patients with oligometastatic or oligoprogressive disease. For metastases that are not suitable for SBRT-regimens, a treatment with 30/40 Gy with simultaneous integrated boost (SIB) in 10 fractions represents a possible regimen. The aim of this study was to investigate the feasibility of this concept and the acute and subacute toxicities. PATIENTS AND METHODS: Clinical records for dose-escalated radiotherapy of all consecutive patients treated with this regimen were evaluated retrospectively (24 patients with 28 target volumes for oncologic outcomes and 25 patients with 29 target volumes for treatment feasibility and dose parameters analysis). Analysis of radiotherapy plans included size of target volumes and dosimetric parameter for target volumes and organs at risk (OAR). Acute and subacute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) V4.0. RESULTS: The most common localization was the spine (71.4%). The most common histology was prostate cancer (45.8%). Oligometastatic or oligoprogressive disease was the indication for dose-escalated radiotherapy in 19/24 patients (79.2%). Treatment was feasible with all patients completing radiotherapy. Acute toxicity grade 1 was documented in 36.0% of the patients. During follow up, one patient underwent surgery due to bone instability. The 1-year local control and patient-related progression-free survival (PFS) were 90.0 ± 6.7% and 33.3 ± 11.6%, respectively. CONCLUSIONS: Dose-escalated hypofractionated radiotherapy with simultaneous integrated boost for bone metastases resulted in good local control with limited acute toxicities. Only one patient required surgical intervention. The regimen represents an alternative to SBRT in selected patients

The Immune Contexture of Liposarcoma and Its Clinical Implications

Simple Summary Liposarcomas (LPS) are malignancies arising from adipose tissue. Based on the histological appearance, five subtypes are distinguished: well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. Immune cells can infiltrate the tumor microenvironment (TME) of LPS and can either promote an efficient antitumor immune response or mediate immunosuppression paving the way for immune evasion of the tumor. The LPS subtypes display different TME characteristics and vary in regard to immune cell infiltration, ranging from the generally lowly infiltrated MLPS to the highly infiltrated DDLPS where immunological determinants predict response to novel antibody-based immunotherapy. Thus, immune cells in the TME can significantly affect response to therapy, disease progression, and patient survival. This review aims to decipher the immune contexture of LPS as well as its clinical association and highlights differences between the LPS subtypes that may have implications for the design of novel treatment strategies. Liposarcomas (LPS) are the most frequent malignancies in the soft tissue sarcoma family and consist of five distinctive histological subtypes, termed well-differentiated LPS, dedifferentiated LPS (DDLPS), myxoid LPS (MLPS), pleomorphic LPS, and myxoid pleomorphic LPS. They display variations in genetic alterations, clinical behavior, and prognostic course. While accumulating evidence implicates a crucial role of the tumor immune contexture in shaping the response to anticancer treatments, the immunological landscape of LPS is highly variable across different subtypes. Thus, DDLPS is characterized by a higher abundance of infiltrating T cells, yet the opposite was reported for MLPS. Interestingly, a recent study indicated that the frequency of pre-existing T cells in soft tissue sarcomas has a predictive value for immune checkpoint inhibitor (CPI) therapy. Additionally, B cells and tertiary lymphoid structures were identified as potential biomarkers for the clinical outcome of LPS patients and response to CPI therapy. Furthermore, it was demonstrated that macrophages, predominantly of M2 polarization, are frequently associated with poor prognosis. An improved understanding of the complex LPS immune contexture enables the design and refinement of novel immunotherapeutic approaches. Here, we summarize recent studies focusing on the clinicopathological, genetic, and immunological determinants of LPS

Prognostic impact of the post-treatment T cell composition and spatial organization in soft tissue sarcoma patients treated with neoadjuvant hyperthermic radio(chemo)therapy

Soft tissue sarcomas (STS) form a heterogeneous group of tumors sharing a mesenchymal origin. Despite good local control of the disease, the occurrence of distant metastases often limits survival of STS patients with localized, high-risk tumors of the extremities. Accumulating evidence suggests a central role for the tumor immune microenvironment in determining the clinical outcome and response to therapy. Thus, it has been reported that STS patients with a high immune signature and especially presence of B cells and tertiary lymphoid structures display improved overall survival and response to checkpoint inhibitor treatment. Here, we explored the effect of curative multimodal therapy on the T cell landscape of STS using multiplex immunohistochemistry. We analyzed the phenotype, frequency, and spatial distribution of STS-infiltrating CD8+ T cells by staining for CD8, 4-1BB, Granzyme B, Ki67, PD-1, and LAG-3 as well as CD3+ T helper cells using a panel consisting of CD3, T-bet, GATA3, RORγT, FoxP3, and Ki67. All patients received neoadjuvant radiotherapy plus locoregional hyperthermia with or without chemotherapy. While the treatment-naïve biopsy sample allows an analysis of baseline T cell infiltration levels, both intra- and peritumoral areas of the matched resected tissue were analyzed to assess composition and spatial distribution of the T cell compartment and its therapeutic modulation. Generally, post-treatment tissues displayed lower frequencies of CD3+ and CD8+ T cells. Association with clinical data revealed that higher post-treatment frequencies of peritumoral and intratumoral CD3+ T cells and intratumoral PD-1+ CD8+ T cells were significantly associated with improved disease-free survival (DFS), while these densities had no prognostic significance in the biopsy. Upon spatial analysis, a high ratio of intratumoral to peritumoral CD8+ T cells emerged as an independent prognostic marker for longer DFS. These results indicate that the STS T cell landscape is altered by multimodal therapy and may influence the clinical outcome of patients. An enhanced understanding of the STS immune architecture and its modulation by neoadjuvant therapy may pave the way towards novel treatment modalities and improve the long-term clinical outcome of STS patients